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ETHICS OF PLACEBO USE IN SCHIZOPHRENIA TRIALS
Abstracts of the 4th Biennial Schizophrenia International Research Conference / Schizophrenia Research 153, Supplement 1 (2014) S1–S384
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participants to the risks associated with the investigational intervention. This is important in the testing of novel interventions in people. People with schizophrenia are also considered to be a vulnerable patient population. Benefit-risk analyses must take into account relevant vulnerabilities (including cognitive and social harm) that create unique risks, as well as the potential for research participants to benefit. If there are scientifically sound methodological reasons to use a placebo control and the risks are reasonable, then it is ethical to for consent. Consent must be valid, which is also an issue in people with schizophrenia. Research participants must be fully informed of alternative available treatment options; the probability they could be randomized to a placebo arm; the consequences of delaying treatment; the risks and benefits associated with the trial; the options to receive treatment if symptoms worsen; and the right to withdraw from the study. Competent research participants are capable of assessing the relative merits and risks of a trial. Denying research participants the option to evaluate a trial and consent to participate is overly paternalistic and a violation of their autonomy. Decisions on whether a vulnerable person or population should be included or excluded from a placebo-controlled trial should be made on a case-by-case basis.
and many experts also consider this methodology as the gold standard of evaluating antipsychotics. This is hotly debated in the field, mostly from an ethical perspective. Yet, there are a number of issues associated mostly with methodological challenges, which only indirectly impinge upon ethical concerns. These include feasibility, patient selection, attitudes and expectations, all of which have an impact on the generalizability of data acquired from placebo controlled clinical trials. Given that there is an increasing difficulty in convincing both patients and clinicians to participate in placebo controlled studies and taking into account high drop out rates in such studies, even in the active treatment arms, the concern has been raised that such data will not be informative for everyday clinical practice.
ETHICS OF PLACEBO USE IN SCHIZOPHRENIA TRIALS
Overall Abstract: In the 19th century, Sigmund Freud already examined the blood of psychotic patients for the presence of infectious agents. At that time, it was the spirochette he searched for, as a sign of tertiary syphilis. Today, tertiary syphilis is rare, but psychiatrists still examine blood samples of patients with psychosis in search for inflammatory or infectious components to rule out Lyme Disease, for example, which can present with psychotic symptoms. The reason for their vigorous search is the important consequences an inflammatory or infectious cause would have for the treatment of these patients. This symposium will provide an update on the long search for an inflammatory component in schizophrenia. We will present recent findings portraying a wide range of scientific approaches (ie proteomics, virology, cognition and RCTs) that investigate the immune hypothesis of schizophrenia. Bob Yolken will present findings from recent investigations on infectious agents in patients with schizophrenia. Faith Dickerson will present findings about the increased risk of schizophrenia associated with infectious and inflammatory markers including IgG antibodies to Toxoplasma gondii, IgG antibodies to gliadin, and C-reactive protein. The third speaker, Sabine Bahn, will provide an overview of recent findings from her lab on the expression of immunological and other protein analytes in peripheral blood, especially providing evidence of the existence of schizophrenia sub-groups. Bart van Berckel will present findings using the PK11195 tracer in PET studies, which identified increased activation of microglia cells in patients with schizophrenia, most pronounced in the medial temporal lobe. Finally, Iris Sommer will review the evidence from RCTs adding different types of anti-inflammatory components to antipsychotic treatment for patients with schizophrenia. All speakers provide evidence for an inflammatory, possibly an infectious cause, in patients with schizophrenia. This suggests that immune modulation could have beneficial effects for (some) patients with schizophrenia. Together, this symposium will provide an overview of the contemporary findings of infectious and inflammatory causes in schizophrenia and provide an update of the current literature on efficacy of anti-inflammatory drugs.
Paul S. Appelbaum Columbia University The ethics of placebo use in schizophrenia research has been a matter of contention for several decades. Opponents of placebo use once relied on the Declaration of Helsinki, which formerly required that “[i]n any medical study, every patient – including those of a control group, if any – should be assured of the best proven diagnostic and therapeutic method”. However, the Declaration now admits the possibility of using placebos, at least in studies in which “no current proven intervention exists; or where for compelling and scientifically sound methodological reasons the use of placebo is necessary to determine the efficacy or safety of an intervention and the patients who receive placebo or no treatment will not be subject to any risk of serious or irreversible harm.” This formulation suggests that two elements are critical to the ethical use of placebos – establishing necessity and minimizing risk – to which obtaining meaningful informed consent of research participants must be added. Necessity may involve any of the following, which may apply to given schizophrenia protocols: standard medications may not be effective with the population under study; the condition being studied is susceptible to substantial fluctuation in severity or to spontaneous remission; the measurement techniques being used in the study are unavoidably imprecise; substantial reduction of risk of exposure to experimental interventions is possible with placebo use; or substantial benefits are likely as a result of more rapidly determining whether the experimental intervention is effective. Minimization of risk can involve: selection of subjects who are less likely to be adversely affected by placebo; minimizing the number of subjects receiving placebo and the duration of its use; making available other forms of treatment during the study that have the potential to mitigate adverse consequences; and having procedures in place for close monitoring of subjects and prompt restoration of active treatment. To insure meaningful consent, investigators may want to screen potential subjects for decisional capacity, use multiple approaches to communicating information, emphasize the potential consequences of being off medication, and quiz potential subjects’ understanding of the study. Placebo use in schizophrenia studies requires clear justification and efforts to minimize harms, but using these approaches can be done in conformance with acceptable ethical standards.
PLACEBO CONTROLLED TRIALS IN PATIENTS SUFFERING FROM SCHIZOPHRENIA: METHODOLOGICAL ISSUES WITH AN INDIRECT EFFECT ON ETHICAL CONSIDERATIONS W. Wolfgang Fleischhacker Medical University Innsbruck, Austria, Department of Psychiatry and Psychotherapy Placebo controlled randomized clinical trials continue to be required by regulatory authorities for the licensing of new drugs for schizophrenia
Symposium THE LONG SEARCH FOR AN INFLAMMATORY COMPONENT IN SCHIZOPHRENIA Chairpersons: Iris Sommer and Sabine Bahn Discussant: Cynthia Shannon-Weickert Sunday, 6 April 2014 4:15 PM – 6:15 PM
META-ANALYSES ON DOUBLE-BLIND RCTS ADDING DRUGS WITH ANTI-INFLAMMATORY PROPERTIES TO ANTIPSYCHOTIC MEDICATION Iris Sommer 1 , Roos van Westrhenen, Marieke Begemann, Lot de Witte, Stefan Leucht, René Kahn 2 1 Department of Psychiatry, University Medical Center, Utrecht, The Netherlands and Rudolf Magnus Institute of Neuroscience, Utrecht, The Netherlands; 2 Brain Center Rudolf Magnus, Dept. Psychiatry, University Medical Center Utrecht Background: The inflammatory hypothesis of schizophrenia is not new, but recently it has regained interest as more data suggest a role of the immune system in the pathogenesis of schizophrenia. If increased inflammation of the brain contributes to the symptoms of schizophrenia, reduction of the inflammatory status could improve the clinical picture. Lately, several trials have been conducted investigating the potential of anti-inflammatory
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participants to the risks associated with the investigational intervention. This is important in the testing of novel interventions in people. People with schizophrenia are also considered to be a vulnerable patient population. Benefit-risk analyses must take into account relevant vulnerabilities (including cognitive and social harm) that create unique risks, as well as the potential for research participants to benefit. If there are scientifically sound methodological reasons to use a placebo control and the risks are reasonable, then it is ethical to for consent. Consent must be valid, which is also an issue in people with schizophrenia. Research participants must be fully informed of alternative available treatment options; the probability they could be randomized to a placebo arm; the consequences of delaying treatment; the risks and benefits associated with the trial; the options to receive treatment if symptoms worsen; and the right to withdraw from the study. Competent research participants are capable of assessing the relative merits and risks of a trial. Denying research participants the option to evaluate a trial and consent to participate is overly paternalistic and a violation of their autonomy. Decisions on whether a vulnerable person or population should be included or excluded from a placebo-controlled trial should be made on a case-by-case basis.
and many experts also consider this methodology as the gold standard of evaluating antipsychotics. This is hotly debated in the field, mostly from an ethical perspective. Yet, there are a number of issues associated mostly with methodological challenges, which only indirectly impinge upon ethical concerns. These include feasibility, patient selection, attitudes and expectations, all of which have an impact on the generalizability of data acquired from placebo controlled clinical trials. Given that there is an increasing difficulty in convincing both patients and clinicians to participate in placebo controlled studies and taking into account high drop out rates in such studies, even in the active treatment arms, the concern has been raised that such data will not be informative for everyday clinical practice.
ETHICS OF PLACEBO USE IN SCHIZOPHRENIA TRIALS
Overall Abstract: In the 19th century, Sigmund Freud already examined the blood of psychotic patients for the presence of infectious agents. At that time, it was the spirochette he searched for, as a sign of tertiary syphilis. Today, tertiary syphilis is rare, but psychiatrists still examine blood samples of patients with psychosis in search for inflammatory or infectious components to rule out Lyme Disease, for example, which can present with psychotic symptoms. The reason for their vigorous search is the important consequences an inflammatory or infectious cause would have for the treatment of these patients. This symposium will provide an update on the long search for an inflammatory component in schizophrenia. We will present recent findings portraying a wide range of scientific approaches (ie proteomics, virology, cognition and RCTs) that investigate the immune hypothesis of schizophrenia. Bob Yolken will present findings from recent investigations on infectious agents in patients with schizophrenia. Faith Dickerson will present findings about the increased risk of schizophrenia associated with infectious and inflammatory markers including IgG antibodies to Toxoplasma gondii, IgG antibodies to gliadin, and C-reactive protein. The third speaker, Sabine Bahn, will provide an overview of recent findings from her lab on the expression of immunological and other protein analytes in peripheral blood, especially providing evidence of the existence of schizophrenia sub-groups. Bart van Berckel will present findings using the PK11195 tracer in PET studies, which identified increased activation of microglia cells in patients with schizophrenia, most pronounced in the medial temporal lobe. Finally, Iris Sommer will review the evidence from RCTs adding different types of anti-inflammatory components to antipsychotic treatment for patients with schizophrenia. All speakers provide evidence for an inflammatory, possibly an infectious cause, in patients with schizophrenia. This suggests that immune modulation could have beneficial effects for (some) patients with schizophrenia. Together, this symposium will provide an overview of the contemporary findings of infectious and inflammatory causes in schizophrenia and provide an update of the current literature on efficacy of anti-inflammatory drugs.
Paul S. Appelbaum Columbia University The ethics of placebo use in schizophrenia research has been a matter of contention for several decades. Opponents of placebo use once relied on the Declaration of Helsinki, which formerly required that “[i]n any medical study, every patient – including those of a control group, if any – should be assured of the best proven diagnostic and therapeutic method”. However, the Declaration now admits the possibility of using placebos, at least in studies in which “no current proven intervention exists; or where for compelling and scientifically sound methodological reasons the use of placebo is necessary to determine the efficacy or safety of an intervention and the patients who receive placebo or no treatment will not be subject to any risk of serious or irreversible harm.” This formulation suggests that two elements are critical to the ethical use of placebos – establishing necessity and minimizing risk – to which obtaining meaningful informed consent of research participants must be added. Necessity may involve any of the following, which may apply to given schizophrenia protocols: standard medications may not be effective with the population under study; the condition being studied is susceptible to substantial fluctuation in severity or to spontaneous remission; the measurement techniques being used in the study are unavoidably imprecise; substantial reduction of risk of exposure to experimental interventions is possible with placebo use; or substantial benefits are likely as a result of more rapidly determining whether the experimental intervention is effective. Minimization of risk can involve: selection of subjects who are less likely to be adversely affected by placebo; minimizing the number of subjects receiving placebo and the duration of its use; making available other forms of treatment during the study that have the potential to mitigate adverse consequences; and having procedures in place for close monitoring of subjects and prompt restoration of active treatment. To insure meaningful consent, investigators may want to screen potential subjects for decisional capacity, use multiple approaches to communicating information, emphasize the potential consequences of being off medication, and quiz potential subjects’ understanding of the study. Placebo use in schizophrenia studies requires clear justification and efforts to minimize harms, but using these approaches can be done in conformance with acceptable ethical standards.
PLACEBO CONTROLLED TRIALS IN PATIENTS SUFFERING FROM SCHIZOPHRENIA: METHODOLOGICAL ISSUES WITH AN INDIRECT EFFECT ON ETHICAL CONSIDERATIONS W. Wolfgang Fleischhacker Medical University Innsbruck, Austria, Department of Psychiatry and Psychotherapy Placebo controlled randomized clinical trials continue to be required by regulatory authorities for the licensing of new drugs for schizophrenia
Symposium THE LONG SEARCH FOR AN INFLAMMATORY COMPONENT IN SCHIZOPHRENIA Chairpersons: Iris Sommer and Sabine Bahn Discussant: Cynthia Shannon-Weickert Sunday, 6 April 2014 4:15 PM – 6:15 PM
META-ANALYSES ON DOUBLE-BLIND RCTS ADDING DRUGS WITH ANTI-INFLAMMATORY PROPERTIES TO ANTIPSYCHOTIC MEDICATION Iris Sommer 1 , Roos van Westrhenen, Marieke Begemann, Lot de Witte, Stefan Leucht, René Kahn 2 1 Department of Psychiatry, University Medical Center, Utrecht, The Netherlands and Rudolf Magnus Institute of Neuroscience, Utrecht, The Netherlands; 2 Brain Center Rudolf Magnus, Dept. Psychiatry, University Medical Center Utrecht Background: The inflammatory hypothesis of schizophrenia is not new, but recently it has regained interest as more data suggest a role of the immune system in the pathogenesis of schizophrenia. If increased inflammation of the brain contributes to the symptoms of schizophrenia, reduction of the inflammatory status could improve the clinical picture. Lately, several trials have been conducted investigating the potential of anti-inflammatory